Brachytherapy seed with fast dissolving matrix for optimal delivery of radionuclides to cancer tissue

ABSTRACT

A system, method and device for treating tumor cells utilizing a resorbable therapy seed made up of microspheres containing a beta- or alpha-particle-emitting radiation source and a resorbable polymer matrix. These seeds are implanted within the tumor and then rapidly dissolved so as to release the microspheres from the polymer matrix. These microspheres then spread within a preselected target area and provide radiation therapy in a predetermined amount and at a preselected rate according the specific needs and necessities of the users. The configuration of the microspheres, the types of radiation provided and the location and use of these microspheres provides desired localized treatment to target cells while preferentially avoiding or minimizing undesired damage to surrounding tissue. The present invention provides a method for making the seeds, as well as a method for utilizing the seeds as a part of the treatment method.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to therapeutic radiology. Moreparticularly, the present invention is directed to radioactive materialscontained in polymers for use in therapeutic applications known asbrachytherapy.

2. Background of the Invention

Treatment of cancerous tissue by exposure to radiation-emitting materialis now a well established and accepted practice. Generally, the aims ofsuch a practice include targeting exposure of radiation to the tissuesurrounding or adjacent to a radiation source while keeping theradiation effects on neighboring healthy tissue to a minimum. A majoradvantage of this form of treatment is that it concentrates the emittedradiation at the site where the treatment is needed, e.g. within oradjacent to a tumor, while keeping the amount of radiation transmittedto the healthy tissue far below what it otherwise would be if theradiation were beamed into the body from an external source, using otherforms of teletherapy.

Prior art forms of brachytherapy typically include various processessuch as placing the source(s) typically small metallic capsules,approximately 4.5 mm long and 0.8 mm in diameter, called seedscontaining a radiation sources such as iodine-125, cesium-131, orpalladium-103, which are placed within the tissue to be treated, i.e.interstitial therapy. In various embodiments of the construction, thecapsule is typically designed to allow the rapid and facile insertion ofthe seed into the organ or body part being treated, with minimal traumato the targeted and surrounding tissues. These devices are many timesinserted into the body percutaneously using a hollow needle which ispreloaded with the desired number of therapy seeds. When the needle isin the desired location in the tissue, a stylet is used to hold theseeds in place while the needle is withdrawn from around them, leavingthe seeds in the desired location. The use of such small radiationsources is a common way of practicing interstitial brachytherapy.

In many such methods it is typically considered necessary and in somecases crucial to enclose the radioactive material with an encapsulatingmaterial so as to contain the radioactive material and preventing itfrom becoming systemically distributed within the patient or escapinginto the environment where it could contaminate medical personnel,medical facilities or the general environment. Various types ofencapsulating devices and materials have been utilized and are presentlycontemplated. Typically these materials contain the radioactive materialwhile allowing photon radiation (Auger x-rays) to irradiate canceroustissues while the radioactive source decays to negligible activity.Typically, the metallic seed remains permanently implanted. A furtherpolymer embodiment containing the radioactive source may graduallydissolve in the body after the radioactive source has decayed tonegligible activity.

Another major drawback for metal-encapsulated seeds is that theencapsulating metal absorbs a significant fraction of the low-energybeta and photon radiation emitted by the contained radioisotope, forexample about 14% of the iodine-125 x-rays and 40% of the palladium-103x-rays are absorbed in the encapsulating metal in the current commercialseeds. As a consequence, to obtain the desired radiation dose rate onthe exterior of the seed, an additional amount of relatively costlyradioisotope activity must be added to overcome the losses in theencapsulating metal. Also, because it is typically necessary to seal (orweld). the ends of the capsules, the effective thickness of the metal isnot the same in all directions resulting in a radiation field around theseed which is not uniform, a fact that complicates treatment planningand raises the possibility of the existence of areas within thetreatment volume in which the radiation dose is non-uniform or belowthat required to kill all tumor cells present.

Thus the current practice of brachytherapy based on the use of discreteencapsulated sources is limited by: the need to associate groups ofdiscrete seeds together by some means so that they can be placed intotissue in a predetermined array and held in that array throughout thetherapeutic life of the sources, the need for complex treatment planningthat takes into account the discrete nature of the seeds and the shapeof the radiation field around each seed with the assumption the fieldshape around each seed is uniformly the same, the need to add excessradioactivity to compensate for the radiation absorption in theencapsulating metal, and the creation of a nonuniform radiation fieldaround the source because the geometry and effective thickness of theencapsulating metal is not the same in all directions, and the radiationfield about a source is not precisely spherical. The present inventionas disclosed herein, significantly reduces each of these limitations andfurthermore allows a more complete realization of the potential benefitsof brachytherapy. The present invention includes a device, method andsystem for implementing brachytherapy and creating devices for use insuch methods and systems. The present invention provides substantialadvantages over the devices taught in the prior art.

Additional advantages and novel features of the present invention willbe set forth as follows and will be readily apparent from thedescriptions and demonstrations set forth herein. Accordingly, thefollowing descriptions of the present invention should be seen asillustrative of the invention and not as limiting in any way.

SUMMARY

The present invention is a method, system and device for treating tumorcells utilizing a resorbable therapy seed comprising microspherescontaining alpha or beta emitting radiation source and a resorbablepolymer matrix containing the microspheres. In use, these seeds areimplanted within the target tissue, such as a prostate carcinoma tumor,and then dissolved so as to release the microspheres so that they arenot encumbered by a surrounding, energy-absorbing material. Thesemicrospheres then slightly spread within a preselected target area andprovide radiation therapy in an amount and at the rate of radioisotopedecay according the specific needs and necessities of the users. Theconfiguration of the microspheres, the types of radiation provided andthe location and use of these microspheres provide desired localizedtreatment to target cancer cells while preferentially avoiding undesireddamage to surrounding tissue. Because beta radiation is defined by adistinct energy-range cutoff, this method combined with the materialsand methods for production of these materials provides a significantlymore effective and less expensive therapy alternative than other methodstaught in the prior art.

In one embodiment of the invention the resorbable therapy seed containsa plurality of microspheres preferably of a generally uniform size, andhaving a diameter of less than 50 microns. While these preferreddescriptions are provided it is to be distinctly understood that thatthe invention is not thereto but may be variously alternatively embodiedaccording the respective needs and necessities of the individual user.Each of these individual microspheres contains a beta particle emittingmaterial such as yttrium-90 preferably bound up in an insoluble chemicalform. While yttrium-90 has been provided as an example of one material,it is to be distinctly understood that the invention is not limitedthereto but may be variously embodied and configured to include avariety of materials including but not limited to phosphorus-32,copper-64, copper-67, iodine-131, lutetium-177, samarium-153,holmium-166, rhenium-186, and rhenium-188. It also includes thealpha-emitters that are usually considered for interstitial radiationtherapy, including but not limited to actinium-225, bismuth-213,bismuth-212, thorium-227, radium-223, astatine-211, and terbium-149.This chemical binding of radioisotope within an insoluble form preventsdissolution and release of the radioactive material in body fluidsleading to translocation to other parts of the body where such radiationis not desired. A colloid form of binding while not required ispreferable.

This beta- or alpha-emitting material is then encapsulated by afast-resorbable polymer that acts to give physical form and rigidity tothe brachytherapy seed, enable surgical placement, and restrain theradioactive material in a desired position and location. In addition tothese microspheres, the resorbable seeds of the present invention alsocontain an imaging material. Various examples of imaging materials maybe utilized including but not limited to metallic, preferably gold,particles. Preferably, these microspheres and these imaging materialsare mixed within a resorbable polymer matrix that holds the materialstogether but can respond, after surgical delivery, to various stimulisuch as temperature, pH, ultrasonic energy, body fluid characteristicsand other influences which increase polymer dissolution rates. Thiscombination can then be pressed or extruded into a shape, preferablyrods and then and cut into individual seeds of a particular preselectedsize. While in some applications the geometry of the particular seed isthat of a cylinder having dimensions appropriate for the use of mosttypical implantation tools, it is to be distinctly understood that theinvention not limited thereto but that a variety of other sizes, shapesand dimensions are also contemplated and may be utilized according tothe needs and necessities of the user. In particular it is contemplatedthat generally flat or slightly convex seeds in any of a variety ofgeometries could be die cut from sheet a flat thin sheet of material mayhave various useful applications depending upon a particular embodiment.Individual seeds can then be coated with a preferably thin, outercoating so as to provide particular advantages consistent with the needsand necessities of the user.

Preferably, the resorbable therapy seed of the present inventionprovides a therapeutic index greater than 1.0, and has an effectivetherapy range that is limited by the range of beta- or alpha-particlesin the seed or target tissue (approximately 1.1 cm for yttrium-90) tolimit therapy doses to target tissues within this range and protectnormal tissue outside of this range from undesirable radiation effects.With these seeds, the method of the present invention can then beperformed. In one embodiment of the invention the method comprises thesteps of implanting a resorbable therapy seed such as those describedabove within a preselected tumor or at a preselected location. Oncesurgically placed, if desired, imaging of the location of the seed canbe accomplished. After the seed has been placed, it is rapidly dissolvedthrough any of a variety of ways depending upon the particular materialthat the polymer matrix is composed of. Thus the dissolution of hismaterial may take place through ultrasonic energy, reaction with theinternal temperature of the body, reaction with a body fluid or any of avariety of other ways. Once the seed polymer encapsulation has beenappropriately placed and dissolved, the radioactive microspheres areappropriately released within the target cancer. These microspheresgenerally remain in place and the beta- or alpha-particles fromradioactive emissions from the microspheres are appropriately deliveredto the target tissues.

The present invention provides a variety of additional advantages overthe prior art. These include but are not limited to better radiationquality for tumor cell killing, a better therapeutic index by reducingthe dose to nearby normal tissues, and therefore the ability to treattumors at higher doses than is taught in the prior art, lower cost formaterials and preparation, resorbable seed materials dissolve into thebody rather than leaving metal pieces in the body, the provision of anouter thin coating that can be variously configured for alternativeembodiments and modalities, the ability of the seed to be degraded byultrasound, and the prevention of unintended migration of the betaemitting material throughout the body.

The purpose of the foregoing abstract is to enable the United StatesPatent and Trademark Office and the public generally, especially thescientists, engineers, and practitioners in the art who are not familiarwith patent or legal terms or phraseology, to determine quickly from acursory inspection the nature and essence of the technical disclosure ofthe application. The abstract is neither intended to define theinvention of the application, which is measured by the claims, nor is itintended to be limiting as to the scope of the invention in any way.Various advantages and novel features of the present invention aredescribed herein and will become further readily apparent to thoseskilled in this art from the following detailed description. In thepreceding and following descriptions I have shown and described only thepreferred embodiment of the invention, by way of illustration of thebest mode contemplated for carrying out the invention. As will berealized, the invention is capable of modification in various respectswithout departing from the invention. Accordingly, the drawings anddescription of the embodiments set forth hereafter are to be regarded asillustrative in nature, and not as restrictive.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a cut-away view of a first embodiment of the device of thepresent invention.

FIG. 2 a is a photograph of a tumor mass without implanted markerspheres.

FIG. 2 b shows directly injected marker spheres in the tumor, imaged byultrasound to demonstrate marker imageability.

FIG. 3 a shows a hypothetical tumor mass within a hypothetical normalmass of tissue.

FIG. 3 b shows the potential placement of resorbable seeds within thehypothetical tumor mass.

FIG. 3 c shows the redistribution of radioactive microspheres afterrapid dissolution of the polymer matrix

FIG. 3 d shows the effective high radiation field around each groupingof radioactive microspheres with sparing of most of the normal tissue.

DETAILED DESCRIPTION OF THE INVENTION

The following description includes the preferred mode of one embodimentof the present invention. It will be clear from this description of theinvention that the invention is not limited to these illustratedembodiments but that the invention also includes a variety ofmodifications and embodiments thereto. Therefore the present descriptionshould be seen as illustrative and not limiting. While the invention issusceptible of various modifications and alternative constructions, itshould be understood, that there is no intention to limit the inventionto the specific form disclosed, but, on the contrary, the invention isto cover all modifications, alternative constructions, and equivalentsfalling within the spirit and scope of the invention as defined in theclaims.

FIGS. 1-3 show various views and embodiments of the present inventionand its implementation. Referring now to FIG. 1, one embodiment of thedevice of the present invention is shown. In this embodiment of theinvention, present invention is a bioresorbable, fast-dissolvingbrachytherapy seed 12. In this embodiment this seed 12 is configured toresemble traditional generally cylindrical brachytherapy seeds(generally having an overall diameter of about 1 mm or less and anoverall length of about 5 mm or less). This seed contains a plurality ofmicrospheres 12. Each of these microspheres 12 contain a beta particleradiation source 14 which is preferably insolubilized in a colloidformulation so as to prevent the undesired dissolution and movement ofthese sources away from a desired location after surgical implantation.In this preferred embodiment, an imaging marker 16 consisting ofmetallic markers are also located within the polymer matrix 18 togetherwith the beta particle microspheres 12 are held within a polymer matrix18. This polymer matrix 18 is configured to dissolve quickly whensubjected to a preselected set of conditions.

Once the seed 10 has been placed and the polymer matrix 18 has beendissolved, the imaging material markers 16 and the beta particlecontaining microspheres 12 migrate to a designated location. Theportions of the microsphere 12 that contain the radiation emissions areremoved and release of radiation energy within the tumor takes place.This allows the radioactive material from inside the seed 12 topartially redistribute within the tumor. In one embodiment, theradioactive source is the beta-emitter yttrium-90, in an insoluble form(phosphate) or colloid, to ensure that the radioactive material does notdissolve in body fluids and redistribute widely throughout the bodyafter release from the resorbable or fast-dissolving seed matrixmaterial 18. This allows the radioactive source 14 to remain in thetumor for localized radiation therapy.

In this preferred embodiment of the invention, the seed 10 isadministered as a solid cylinder by conventional surgical(intraoperative) seed-placement mechanisms and grids. The seed 10 alsocontains imageable markers 16 to allow the surgeon placing the seed tovisualize seed placement within the tumor using ultrasound, magneticresonance imaging, CT-imaging, or fluoroscopy. The fast-dissolvingmatrix 18 allows beta-emitters to be used with greater flexibility andenergy-delivery efficiency than if the radionuclide were to be containedwithin a slow-dissolving polymer or metallic (non-resorbable) seedexterior. Use of beta- or alpha-emitting radionuclides with well-definedrange and cut-off distance enables a higher radiation absorbed dose tobe delivered to tumors, relative to conventional seed brachytherapyusing Auger-electron emitters, without exceeding the normal tissuetolerance of surrounding normal tissues and organs for improvedtumor-irradiation efficacy.

The embodiment of the invention described herein allows delivery of theencased radioactive source material to the tumor without loss bycontamination prior to delivery, protects hospital workers and thepatient from loose contamination, or spread into the environment asradioactive contamination, rapidly dissolves in the tumor after surgicalplacement, and can be easily formable into a desired size, (In thepreferred embodiment this is generally a cylinder shape with a diameterof 0.5 to 0.8 mm and a length of about 4.5 to 5 mm). Two different kindsof technology will be employed for extruding or pressing the seed,however it is to be distinctly understood that the invention is notlimited thereto but may be variously embodied according to the needs andnecessities of a user.

In one method of preparing the seeds, a wet granule preparation processis utilized. In this embodiment all seed materials, including theradioactive source 14, gold markers 16, and rapidly dissolvingexcipients 18-mixed together with proper solvents are combined for forma mixture. This mixture is then extruded against a desired size sieveand dried in an oven. These extruded sections can then be cut into seedsof a desired size and if desired coated with a coating material 20. Thesecond method for preparing the brachytherapy granules involves directlycompressing the seeds from the dry mixture of radiation source 14,imaging materials 16, and polymer matrix 18, using a mechanical,high-force tablet press. This direct compression method is generallypreferred, however if the mixed material is powder and difficult toprepare to make granules by direct compression method, the previouslydescribed wet method will be the preferred alternative.

In this embodiment of the present invention the matrix 18 containing theradioactive source 14 and marker material 16 dissolves quickly (minutesto hours) to release the radioactive source 14 in tumor tissue afterplacement. This is dramatically shorter than prior art seeds whichtypically require weeks to months to dissolve. The dissolution of thepolymer matrix 18 can be variously configured according to the needs ofthe user. Various types of stimuli can be utilized to accomplish thisdissolution including but not limited to heat, ultrasound, body fluid,and other stimuli. Similar types of stimuli can be utilized to affectthe coating 20 of the seed.

In one embodiment of the invention the polymer matrix 18 is one thatdisintegrates rapidly in water or body fluids. In another embodiment ofthe invention the polymer-matrix 18 is a temperature-induced orthermally stimulated, rapidly dissolving system. Various polymermaterials may be included in these matrices depending upon theparticular needs of the individuals involved. While various materialscan be utilized, typical polymers such as PLA (poly lactic acid) andPLGA (copoly lactic acid/glycolic acid are envisioned. Typical PLA andPLGA biodegradable polymers have molecular weights ranging from 5,000 to100,000. They are also available as mixtures of PLA and PLGA, forexample 75%/25% or 50%/50%. They may constitute 0.5 percent to 5 percentof the seed. When pressed with sorbitol, the major inert part of theseed, the polymers bind the sorbitol into a hard form or shape, and alsoprovide a protective coating about the sorbitol. The sorbitol is astandard inert pharmaceutical additive for pills. In such embodiments abeta-particle-emitting radionuclide, such as yttrium-90, rhenium-186,rhenium-188, or lutetium-177 is utilized as insoluble colloid ormicrosphere 12. In addition, alpha emitters such as actinium-225,bismuth-213, bismuth-212, thorium-227, radium-223, astatine-211, orterbium-149 could also be used as the active agent. These seeds 10 alsomay contain markers such as radioactive gold-198 or gold-197, or withstable gold markers, as well as anti-inflammatory agents such asibuprofen, florabioprofen, aspirin, acetaminophen, endocen, toridol,voltren, telecten, and ketoprofen. The polymers, sorbitol, activeagents, markers and anti-inflammatory agents would be produced orprepared under good manufacturing practices (controlled for sterilityand apyrogenicity). These formulations will serve as brachytherapy andposition-monitoring source materials for imaging—for example byultrasound or gamma-camera imaging system common to nuclear medicineclinics. In some other embodiments and applications dissolution of thepolymer matrices may be enhanced by the user of 1 to 3 MHz ultrasound onthe site of tumor after localizing the seeds 10 to enhance the break-upand dissolution of the seed matrix.

In experiments embodiments of the present invention the microspheres ofthe present invention were included in tablets containing sorbitol andeither a biodegradable or non biodegradable polymer. While variousmaterials can be utilized, examples of various polymers such as PLA(poly lactic acid) and PLGA (copoly lactic acid/glycolic acid areenvisioned. The exact concentration of and size of the polymer werevariously altered to affect the rate of dissolution of the material. Inthe experiments it was found that tablets containing the inertingredient sorbitol coated with a 2 percent (30,000 MW) biodegradablepolymers such as PLA (poly lactic acid) or combinations of poly lacticacid and PLGA (copoly lactic acid/glycolic acid) dissolved most quicklyin water, while another formulation having 0.5% of the same polymerabsorbed most quickly in tissue studies. Tablets using varyingconcentrations of less biodegradable materials such as the ammoniomethacrylate copolymers sold under the tradename EUDRAGIT RL andEUDRAGIT RZ dissolved much more slowly. Depending upon the desiredcharacteristics to be imparted to the particular tablet, the type,concentration, formulation and configuration of the particularingredients may be variously and appropriately modified according to theneeds and necessities of the user.

In one preferred formulation a water or body fluid dissolvable polymermatrix 18 includes crospovidone (N-vinyl-2-pyrrolidone) sold under thetrade name Polyplasdone® XL-10, International Specialty Products Wayne,N.J. USA. In addition to this material, a variety of other types ofmaterials may also be utilized to bring about a similar result. Examplesof such other materials include but are not limited topolyvinylpyrrolidone, starch, alginic acid, formaldehyde, calciumcarboxymethyl cellulose, sodium starch glycolate, and sodiumcarboxymethyl cellulose.

In addition to these materials, cellulose derivatives may also serve asan excipient. These include hydroxypropylmethylcellulose, such as thosesold under the trade names “TC-5E”, “Metolose 90”, “Metolose 65SH”,trade names; produced by Shin-Etsu Chemical Co., Ltd. Tokyo, Japan),hydroxypropylcellulose (for example, “Nisso HPC”, trade name; producedby Nippon Soda Co., Ltd. Tokyo, Japan), methyl cellulose (for example,“Metolose SM”, trade name; produced by Shin-Etsu Chemical Co., Ltd.,Tokyo, Japan), and hydroxyethylcellulose (“NATROSOL”, trade name;produced by Hercules Japan, Ltd., Tokyo Japan). More preferred ishydroxypropylmethylcellulose.

Various soluble diluents agents may be required for the wet preppingprocess of the invention these include but are not limited to a solublediluent with binding properties that consist of a polyol having lessthan 13 carbon atoms and being either in the form of the directlycompressible product with an average particle diameter of 100 to 500micrometers, or in the form of a dry powder with an average particlediameter of less than 100 micrometers. Preferably, this polyol isselected from the group comprising mannitol, xylitol, sorbitol andmaltitol. In addition to these materials, the addition of a lubricantused in the fast release formulation may also be utilized. Examples ofsuch lubricants include conventional lubricants, such as magnesiumstearate, sodium dodecyl sulfate. Generally, it is preferred that thelubricant be water soluble. Hence, the preferred lubricant is sodiumdodecyl sulfate in an amount ranging from about 1 to 3 percent.

In a second embodiment of the present invention the polymer based matrixis a temperature-sensitive rapid disintegrating formulation.Temperature-sensitive, rapid-dissolving formulations, are preferablymade from materials that are in a generally solid state at roomtemperature and provide sufficient rigidity to allow injection of a seedmade from such material into the tumor tissue. This material preferablywould then dissolve in the tumor site at 37-42 degrees C. Ultrasoundtreatment can be used to increase local material temperature.Formulation matrices can be oleophilic bases and/or water-soluble bases,and can be used in combination. Examples of oleophilic bases includecacao butter, lanolin fat and hard fats. Examples of the hard fatsinclude: Witepsol, tradename, manufactured by Huls Inc.), Suppocire,tradename, (manufactured by Gattefosse Inc.), Isocacao, tradename,(manufactured by Kao Corp.), and tradename, Pharmasol (manufactured byNOF Corp.), etc.

In most preferred embodiments of the present invention the beta- oralpha-emitting radiation source has a generally short half-life (lessthan 60 days, and preferably less than 9 days). More specifically, incertain cases the radioisotope is selected from the group of yttrium-90,phosphorus-32, copper-64, copper-67, iodine-131, lutetium-177,samarium-153, holmitim-166, rhenium-186, rhenium-188, and combinationsthereof. Beta particles have short path length in tissue, whichindicates minimal irradiation of surrounding normal tissue. In addition,these beta emitting radiation sources are generally confined to aspecific target tissue. Alpha particle ranges are even shorter(typically 40 to 80 micrometers in tissue.

The purpose of the radioactive confine is to minimize or preventmigration of the radioisotope to healthy tissue areas. The radioisotopemay be confined, for example, by chelators or complexing agents,capsules, and combinations thereof. Examples of useful isotope/chelatorcombinations are, for example, yttrium-90 with1,4,7,10-tetraazacyclododecane-N,N′,N″,N′″-tetraacetic acid (DOTA),derivatives of DOTA. In addition to these materials insoluble salts suchas 90-yttrium phosphate may also be utilized. It is preferred thatparticles of the insoluble salt are hydrothermally synthesized insolution as the disperse phase of a colloid. As used herein a colloid isa chemical system composed of a continuous medium (continuous phase)throughout which are distributed small particles, for example about0.0001 micrometer to about 3 micrometer in size (the disperse phase).Hydrothermal synthesis refers to the synthesis of products by reactingreagents in solution at temperatures and/or pressures above ambienttemperature and/or pressure, such as by performing the reaction in asealed vessel (generally known as a hydrothermal bomb) that may also beheated. The hydrothermal bomb may include a liner in which reagents arereacted so that the bomb can more easily be reused.

Hydrothermal synthesis of insoluble salt particles containing theradioactive agent allows for control of particle shape and/or size.While uniform size and shape are not required, these characteristics canaid in determining the amount of radioactive agent to administer toachieve a particular dose of radiation to tissue in vivo. That is themore uniform the particles are in size and/or shape the more consistentthe radiation doses for a particular amount of particles because similarsized and/or shaped particles provide similar amounts of radiation.

Certain embodiments of hydrothermal syntheses of insoluble saltradioactive therapeutic agents, such as YPO.sub.4 particles, include acomplexing agent, such as a compound comprising ethylene diaminetetraacetic acid (EDTA), to bind metal cations, such as Y.sup.3+, insolution, allowing the cations to exceed the saturation concentrationwithout significant precipitation of the salt. During hydrothermalsynthesis the EDTA releases the cations to react with anions, such asYPO.sub.4.sup.3−, to form particles. In certain embodiments theparticles formed are colloidal, that is, the particles form a dispersephase of a colloid in the continuous phase of the solution.

In certain embodiments, colloids including YPO.sub.4 particles as thedisperse phase are synthesized using EDTA, an yttrium (Y) source, and aphosphate (PO.sub.4) source, all reacted in a hydrothermal bomb.Preferably the seeds in the preferred embodiment also include an imagingmaterial such as a metallic marking material. In one preferredembodiment gold particles were utilized as an ultrasound marker orcontrast agent. The presence of these marking materials allows placementof the seeds in the tissue to be verified and monitored through the useof ultrasound imaging, magnetic resonance imaging, x-ray fluoroscopy, orother standard medical imaging modality. Examples of such images areshown in FIG. 2 a-b. FIG. 2 a shows a tumor ultrasound images beforemarker placement, and FIG. 2 b shows a tumor ultrasound image afterplacement of spherical markers into a mouse tumor. Thus this materialwhen combined with the seed matrix, could render the brachytherapy seedssufficiently imageable via ultrasound for practical application as anaid to surgical placement in tumor tissue. The images also allow thesurgeon to verify that the seed are correctly place in the targettissue.

While ultrasound imaging is described herein it is to be distinctlyunderstood that the imaging step is not limited thereto but may bevariously embodied and configured according to the needs and necessitiesof the user. If necessary, ultrasound may also be used to enhance matrixdissolution This can be done utilizing a tissue-warming device such as aOmnisound 3000 commercialized ultrasound machine with 1 MHz and 3 MHzsignals, that modify the power density, duty cycle, and wave irradiationtime to optimize the brachytherapy seed dissolution.

In one example of the present invention, seeds 12 as described above areimplanted into a selected portion of tumor tissue. The tumor ispreferably imaged to verify placement of the seeds in the desiredlocation. After this imaging has taken place, the seeds are dissolvedand microparticles that contain the beta- or alpha-emitting source arethen released to provide therapeutic radiation to the tumor to destroythe unwanted tumor tissue. This method provides several advantages.First, this method provides a user the ability to use inexpensivematerials as the seed matrix, radioisotope, and markers. Second, thisless expensive seed has the ability to deliver higher localizedradiation doses to radiation-insensitive solid tumors (which couldinclude cancers of the liver, pancreas, brain, kidney, head and neck,prostate, colon, and others, or solid tumors that are not resectable andthat must be treated effectively without surgical removal, such as thosethat may surround major blood vessels, the vocal chords or spinal columnnerves. The present invention provides an ability to use radioisotopesother than the more common Auger-electron-emitters traditionally used inseed brachytherapy, such as iodine-125, paladium-103, and cesium-131,which are all relatively expensive to produce. The present inventionalso provides the ability to deliver more locally intense radiationdoses to tumor tissues than achieved using the Auger-electron emittersmentioned above.

While various preferred embodiments of the invention are shown anddescribed, it is to be distinctly understood that this invention is notlimited thereto but may be variously embodied to practice within thescope of the following claims. From the foregoing description, it willbe apparent that various changes may be made without departing from thespirit and scope of the invention as defined by the following claims.

1. A resorbable therapy seed comprising: at least two microspheres eachcontaining an active particle-emitting radiation source; and aresorbable polymer matrix containing said microspheres.
 2. Theresorbable therapy seed of claim 1 wherein said active particle emittingradiation source is a beta emitting source.
 3. The resorbable therapyseed of claim 1 wherein said active particle emitting radiation sourceis an alpha emitting source.
 4. The resorbable therapy seed of claims 2or 3 further comprising a thin protective coating over said resorbablepolymer matrix.
 5. The resorbable therapy seed of claims 2 or 3 furthercomprising an imaging material.
 6. The resorbable therapy seed of claims2 or 3 further comprising an anti-inflammatory agent.
 7. The resorbabletherapy seed of claim 5 wherein said imaging material includes metallicmicrospheres having a diameter less than 50 microns.
 8. The resorbabletherapy seed of claim 1 wherein said active particle radiation emittingsource is bound as an insoluble material within said microsphere.
 9. Theresorbable therapy seed of claim 2 wherein said beta-emitting source isselected from the group consisting of yttrium-90, phosphorus-32,copper-64, copper-67, iodine-131, lutetium-177, samarium-153,holmium-166, rhenium-186, rhenium-188, and combinations thereof.
 10. Theresorbable therapy seed of claim 3 wherein said alpha-emitters areselected from the group consisting of actinium-225, bismuth-213,bismuth-212, thorium-227, radium-223, astatine-211, and terbium-149. 11.The resorbable therapy seed of claim 1 wherein said therapy seedprovides a therapeutic index greater than 1.0.
 12. The resorbabletherapy seed of claim 1 further comprising an imaging materialcomprising metallic microspheres and a coating over said seed whereinsaid emitting source is bound as an insoluble material to preventmovement of said radioactive source beyond a preselected targetlocation.
 13. The resorbable therapy seed of claim 1 wherein saidresorbable polymer matrix is capable of dissolution by ultrasonicenergy.
 14. The resorbable therapy seed of claim 1 wherein saidresorbable polymer matrix is capable of dissolution by body fluids. 15.The resorbable therapy seed of claim 1 wherein said resorbable polymermatrix is capable of dissolution by the natural temperature of the bodyrelative to room temperature.
 16. A method for manufacturing resorbabletherapy seeds characterized by the step of: mixing preselectedquantities of a radiation emitting source in a resorbable matrix-formingpolymer material.
 17. The method of claim 16 wherein said mixing stepfurther comprises mixing an imaging material with said radiationemitting source within said resorbable matrix-forming polymer material.18. The method of claim 17 further comprising the step of extruding amixture of said beta emitting source said resorbable matrix polymermaterial into rods.
 19. The method of claim 18 further comprising thestep of cutting said extruded mixture into seed pieces having apreselected size.
 20. The method of claim 19 further comprising the stepof coating said seed pieces having a preselected size.
 21. A method forforming a resorbable brachytherapy seed comprising the steps of coatinginert sorbitol powders with poly lactic acid or copoly lacticacid/glycolic acid, mixed with a radioactive agent and an imaging agent,and compressing said coated powder s into a seed shape.
 22. A method fortreating a tumor characterized by the step of: implanting a resorbabletherapy seed having a microspherical particles having a beta-emittingsource within a resorbable polymer matrix within a tumor.
 23. The methodof claim 20 further comprising the step of dissolving said polymermatrix using ultrasonic energy.
 24. The method of claim 20 furthercomprising the step of dissolving said polymer matrix using body fluids.25. The method of claim 20 further comprising the step of dissolvingsaid polymer matrix using body temperature?
 26. The method of claim 20wherein said resorbable therapy seed further comprises an imaging mediaand wherein said method further comprises the step of imaging said tumorto verify placement of said seeds prior to dissolving said polymermatrix using ultrasonic energy and body fluids.
 27. A resorbable therapyseed comprising: at least two microspheres each containing a betaparticle-emitting radiation source; and a resorbable polymer matrixcontaining said microspheres, said resorbable polymer matrix containingat least one biodegradeable polymer material.
 28. A resorbable therapyseed comprising: at least two microspheres each containing an alphaparticle-emitting radiation source; and a resorbable polymer matrixcontaining said microspheres, said resorbable polymer matrix containingat least one biodegradeable polymer material.